Lower alkyl reserpate omicron-



United States Patent LOWER ALKYL RESERPATE O-(DIALKYL-l- ALKENOXYBENZOATES) Jacob' Szmuszkovicz, Portage Township, Kalamazoo County, and Richard V. Heinzelman, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan g No Drawing, Application March 3, 1958 Serial No. 718,450

11 Claims. 0. 260-287) The present invention is concerned with physiologically active chemical compounds related to reserpine and is more particularly concerned with methyl reserpate O-(dia1kyl-4-alkenoxybenzoates) represented by the following formula:

CHsO N III,

alkyl CH=O O-alkenyl O 1H alkyl Of particular interest are compounds of the foregoing formula wherein the alkyl radicals and alkenyl radical are the same or diiferent lower-alkyl radicals and lower alkenyl radical, respectively, the terms lower-alkyl and lower-alkenyl being defined in this specification and appended claims, respectively, as an alkyl radical contain ing from one to six carbon atoms, inclusive, and an al-' kenyl radical containing from three to four carbon atoms, inclusive. The methylreserpate O-(dialltyl-4-alkenoxybenzoates) of this invention are prepared by esterificat'ior'i of methyl reserpate with an esterifying agent to introduce a dialkyl-4- alkenoxybenzoate radical, as more fully illustrated by the examples.

It is an object of the present invention to provide methyl reserpate O-(dialkyl 4 alkenoxybenzoates), particularly the methyl reserpate O-[di-(lower-'alkyl)-4-(lower*alkenoxy)-benzoates], which are physiologically active agents of high potency having hypotensive and sedative proper ties and which have a superior ratio of hypotensive'to sedative activity and a" superior therapeutic ratio when compared with reserpine. The compounds of the present invention can be substituted for reserpine in known reser pine-containing pharmaceutical compositions such as tablets, injectables, and elixirs. Other objects and uses of the present invention will be apparent to one skilled in the art. g

' In-this invention, representative O-estrs of methyl reserpate include the 2,6-dimethyl-4-allyloxybenzoate, 2,6-dimethyl-4-propenoxybenzoate, 2,6-dimethyl-4- fl-butenox y) -benzoate, 2,6-dimethyl-4-(B-isobutenoxy) -benzoate, 2,6-dimethy1-4-(B-Secondary-butenoxy)-benzoate, 2,6-diethyl-4-al1y1oxybenzoate, 2,6-dibutyl-4-allyloxybenzoate, V 2-methyl-6-ethyl-4-allyloxybenzoate, and other 2,6-dialkyl- 4-alkenoxybenzoates, the 3,5-dimethyl-4-allyloxybenzoate, 3,5-dimethyl-4-(p-butenoxy)-benzoate, 3,5-diethyl- 4;(a-butenoxy)-benzoate,

2,933,499 I Patented Apr. 19, 1960 'ice 2 3,i dipropyl 4-allyloxybenzoate, 3,5-dihexyl-4propenoxybenzoate, 3,5-dipropyl-4-(fl-isobutenoxy)-benzoate, and other 3,5-

dialkyl-4-alkenoxybenzoates, the 2,3-dimethyl-4-allyloxybenzoate, 2,3-dimethyl-4-(B-butenoxy)-benzoate, 2,3-dimethyl-4-(B-secondary-butenoxy)-benzoate, 2-inethyl-3-ethyl-4-allyloxybenzoate, 2,-3-diisobutyl-4-(B-butenoxy)-benzoate, and other 2,3-

dialkyl-4-alkenoxybenzoates, the Z-isopropyl-S-methyl-4-allyloxybenzoate, 2-methyl-5-isopropyl-4-allyloxybenzoate, 2,5-dipropyl-4-allyloxybenzoate, 2,5-dimethyl-4-allyloxybenzoate, 2,S-diethyl-4-propenoxybenzoate, 2-methyl-5-isopropyl-4- (fl-butenoxy) -benzoate,

and other 2,5-dialkyll-alkenoxybenzoates, particularly those dialkyl-4-alkenoxybenzoates wherein the alkyl radicals each contain less than seven carbon atoms and the alkenoxy radical contains from three to four carbon atoms, inclusive, the 2,6-dimethyl-4-alkenoxy-benzoates and 3,S-dipropyl-4-alkenoxybenzoates of this class wherein the alkenoxy radicals are fi-alkenoxy radicals in general being more particularly preferred. The 2,6-dirnethyl- 4-allyloxybenzoate and 3,5-dipropy1-4-allyloxybenzoate esters in general are still more preferred, the most preferred compound being the 3,5-dipropyl-4-allyloxybenzo: ate ester. It is to be understood that within the scope of thisinvention are included the methyl reserpate O-(dialkyl-4-alkenoxybeuzoate) free base and acid addition salts thereof such as the sulfates, hydrochloride, phosphates, hydrobromide, hydroiodide, acetate, propionate, benzoate, citrates, maleates, succinates, salicylate, phenylonate, etc. v

In preparing the methyl reserpate O-esters of this invention the preferred esterifying agent is the acid chloride of the dialkyl-4-alkenoxybenzoic acid. However, if desired, the acid bromide, or the acid anhydride, or other dialkyll-alkenoxybenzoic acid compound suitable for esterificajtion of methyl reserpa'te can be employed, all these 'dialkyl-4-alkenoxybenzoic acid compounds being prepared from the dialkyl-4-alkenoxybenzoic acid by con- 4falkenoxybenzoic acid with thionyl chloride provides the corresponding di'alkyl-4-alkenoxybenzoyl chloride. The dialkyl-4-alkenoxybenzoic acids, in turn, are prepared by prior art procedures or procedures analogous thereto, for example, dialkyl-4-hydroxybenzoic acids (US. Patent 2,- 243,694) are converted, via their esters, to dialkyl-4- alkenoxybenzoic acids by conventional etherification and hydrolysis procedures well-known in the art. The 2,3- dialkyland 2,6-dialkyl-4-hydroxybenzoic acids are obtained, for example, by aromatization, such as by heating in the presence of a palladium catalyst, of corresponding 2,3-dia'lkyland 2,6-dialkyl-4-oxo-Z-cyclohexene-l-carboxyli'c acid esters (US. Patent 2,5 82,252 and copending application S.N. 432,033, filed May 24, 1954), followed by hydrolysis of the resulting 2,3-dialkyland 2,6-dialkyl- 4-hydroxybenzoic acid esters. The 2,5-dialkyl-4-alkenoxybenzoic acids are obtained, for example, by nitration of 1,4-dialkylbenzenes to produce Z-nitro-1,4-dialkylbenzenes, the nitro group then being reduced to an amino group which is diazotized and hydrolyzed to a hydroxy group, and the thus-obtained 2,5-dia1kylphenol etheriiied to produce 2,5-dialkyl-1-alkoxybenzenes which are chloromethylated in the 4-position, the chloromethyl group then converted to a carboxyl group, for example, by alkaline hydrolysis of the chloromethyl group to a hydroxymethyl group followed by oxidation of the hydroxymethyl group to a earboxyl group with potassium permanganate, the;

acetate, a'and fi-phenylpropionates, ,B-cyclopentylpropiventional procedures, for example, reaction of a dialkyl- V are obtained, for example, fromA-chlorophenol by acylation in the Z-position, for example, with an acyl chloride and aluminum chloride according to the Friedel-Crafts acylation method, reduction of the 2-acyl radical to an alkyl radical, for example, with zinc and hydrochloric acid according to the Clemmensen reduction method, acylation, as described above, of the thus-produced 2-alkyl-4-chlorophenol in the 6-position followed by reduction of the acyl radical, as described above, to produce 2,6-dialkyl-4- chlorophenol, elimination of the 4 -chloro atom, for exam ple, by treatment with sodium and alcohol, alkylation of the phenolic hydroxyl group to obtain 2,6-dialkyl-1-al koxybenzene, introduction of a 4-carboxyl radical, for example, by 4-bromination followed by Grignard reagent formation with magnesium and subsequent treatment with carbon dioxide, to obtain 3,5-dialkyl-4-alkoxybenzoic acid which on acid hydrolysis of the 4-alkoxy radical, followed by esterification of the carboxyl group, reetherification of the 4-hydroxy group to introduce a 4-alkenoxy radical, as described above, and hydrolysis of the ester,

provides the desired 3,5-dialkyl-4-alkenoxybenzoic acid.- 3,5-dialkyl-4-alkenoxybenzoic acids also are obtained bydiazotiza'tion and acid hydrolysis of the corresponding alumina.

4 ate) is eluted with benzene containing twelve percent chloroform, and, on evaporation of solvent, the compound is obtained as a yellow powder which does not readily crystallize. Example 3.Methyl reserpate 0-[2-methyl-6-ethyl-4-(flbutenoxy)-benz0ate] I Methyl reserpate is esterified with2-methyl-6-ethyl-4- (fl-butenoxy)-benzoyl chloride according to thegeneral procedure of Example 1. The resulting crude product is dissolved in benzene and chromatographed over neutral The methyl reserpate O-[2-methyl-6-ethyl-4- (,B-butenoxy)-benzoate] is eluted with benzene contain- 3,5-dialkyl-4-aminobenzoic acid followed by ctherification,

Example I .Methyl reserpate 0-(dialkyl-4-alkenoxybenz0aze)preferred general procedure A cold solution of 4.14 grams (0.01 mole) of methyl reserpate in fifty milliliters of pyridine is prepared and 0.03 mole of the dialkyl-4-alkenoxybenzoyl chloride is added thereto during'a five-minute period with stirring.

The resulting reaction mixture is maintained at room temperature (between about fifteen and about 35 degrees centigrade) for approximately twenty hours. Then the reaction mixture is cooled in an ice bath and a mixture of 100 milliliters of water and fifty grams of ice is added with stirring. The aqueous-organic mixture is extracted with four SO-milliliter portions of chloroform. The combined chloroform extracts are washed with'four SO-milliliter portions of five percent aqueous potassium hydroxide.

solution and the combined aqueous alkaline wash solutions are extracted 'once with fifty milliliters of chloroform. The combined chloroform solutions then are washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent the solution is evaporated to dryness under reduced pressure. Theresidual crude methyl reserpate0-(dialkyl-4-alkenoxybenzoate) is purified by crystallization and/or chromatographic procedures in a conventional manner.

Example 2.Methyl reserpate 0-(2,6-dimethyl-4-allyloxybenzoate) Methyl reserpate is esterified with 2,6-dimethyl-4-allyloxybenzoyl chloride according to the general procedure of Example 1. obtained is dissolved in thirty milliliters of benzene and chromatographed over 300 grams of neutral alumina.

The methyl reserpate O-(2,6-dimethyl-4-allyloxybenzo The crude dark brown solid (8.1 grams) ing ten to fifteen percent chloroform, and, on evaporation of solvent, is obtained as a non-crystalline solid.

Example 4.M ethyl reserpate O-(3,5-dipr0pyl-4-allyl0xybenzoate) Following the general procedure of Example 1 methyl reserpate is esterified with 3,5-di-(n-propyl)-4-allyloxybenzoyl chloride (a special methodfor the production of the corresponding acid is described in copending application Serial No. 603,236, filed August 10, 1956) to produce twelve grams of crude methyl reserpate O-(3.5-dipropyl-4-allyloxybenzoate). The compound, dissolved in benzene, is purified by chromatographing over 300 grams of neutral alumina, the purified ester being eluted with benzene containing twenty percent chloroform. The solvent is removed by evaporation. The ester thus obtained is crystallized by trituration with ether and is recrystallized from benzene-petroleum ether (boiling point 30 to 60 degrees centigrade) mixture. The recrystallized methyl reserpate O-(3,5-dipropyl-4-allyloxybenzoate) melts at 203 to 204 degrees centigrade.

Analysis.-Calcd for C i-1 N 0 C, 71.10; H, 7.65; N, 4.25. Found: C, 71.42; H, 7.35; N, 4.29.

Example 5.--Methyl reserpate 0-(2-methyl-3-ethyl-4-allyloxy-benzoate) Methyl reserpate is esterified with 2-methyl-3-ethyl-4- allyloxybenzoyl chloride according to the general procedure of Example 1 to produce methyl reserpate 0-(2- methyl-3-ethyl-4-allyloxybenzoate) Example 6 .-M ethyl reserpate 0-(Z-methyl-S-isopropyk 4-allyloxybenz0ate) According to the general procedure of Example 1, methyl reserpate is esterified with Z-methyI-S-isopropyl- 4-allyloxybenzoyl chloride to produce methyl reserpate O-(2-methyl-5-isopropyl-4-allyloxybenzoate) In'the same manner as shown in Examples 1 through 6 other methyl reserpate O-(dialkyl-4-alkenoxybenzoates) are prepared from methyl reserpate and the appropriate acid chloride esterifying agent, including the following 0- esters of methyl reserpate: 2,6-dimethyl-4-propenoxybenzoate,- 2,6-dimethyl-4-(,B-butenoxy)-benzoate, 2,6-dimethyl-4- fl-isobutenoxy) -benzoate, 2,6 diethyl-4-(13-secondary butenoxy) benzoate, 2,6-dibutyl-4-allyloxybenzoate, 3,5-dimethyl-4-allyloxybenzoate, 3,5-dimethyl-4-(ebutenoxy)-benzoate, 3,5-diethyl-4-allyloxybenzoate, 3,5- dihexyl-4-(' -butenoxy)-benzoate, 3,5-dipropyl-4-(p-isobutenoxy)-benzoate, 2,3-dimethyl-4-allyloxybenzoate, 2- methyl-3-ethyl-(fl-butenoxy)benzoate, 2,3-diisobutyl-4- (p-isobutenoxy) benzoate, 2-isopropyl-5-methyl-4-allyloxybenzoate, 2,5-dipropyl-4-allyloxybenzoate, 2,5-dimethyl-4-allyloxybenzoate, 2,5-diethy1-4-allyloxybenzoate, 2-methyl-5-isopropyl-4-propenoxybenzoate, and other 2,3-, 2,5-, 2,6-, and 3,5-dialkyl-4-alkenoxybenzoates. By substituting other alkyl reserpates, for example, ethyl reserpate, propyl reserpate, butyl reserpate, isobutyl reserpate, hexyl reserpate, etc. there are obtained the'corresponding O-(dialkyl-4-alkenoxybenzoates)1 which have like utility.

Following the procedures of Examples 1 through 6, but

' substituting methyl deserpidate, methyl raunescate or methyl raujemidate for the methyl reserpate, there are zoate) esters of methyl deserpidate, methyl raunescate, and methyl raujemidate, respectively, wherein the ester radicals are those named previously in the description and examples, which esters are useful for the same purpose and employed in the same manner as the corresponding O-(dialkylA-alkenoxybenzoate) esters of methyl reserpate. The following examples are illustrative:

Example 7.Methyl deserpidate -(3,5-dipr0pyl-4- allyloxybenzoare) Following the procedure of Example 1 using methyl deserpidate in place of methyl reserpate and 3,5-dipropyl- 4-allyloxybenzoyl chloride as the dialkyl-4-alkenoxyben zoyl chloride, there is obtained methyl deserpidate O-(3,5- dipropyl-4-alloxyb enzoate) Example 8.-Methyl raunescate O-(3,5-dipropyl-4- allyloxybenzoate) Following the procedure of Example 1 using methyl raunescate in place of methyl reserpate and 3,5-dipropyl- 4-allyloxybenzoyl chloride as the dialkyl-4-alkenoxybenzoyl chloride, there is obtained methyl raunescate O- 3,5 -dipropyl-4-alloyloxyb enzoate) Example 9.Melhyl rauiemidate 0-(3,5-dipropyl-4- alloyloxybenzoate) Following the procedure of Example 1 using methyl raujemidate in place of methyl reserpate and 3,5-dipropyl- 4-allyloxybenzoyl chloride as the dialkyl-4-alkenoxybenzoyl chloride, there is obtained methyl raujemidate O- (3,5-dipropyl-4-allyloxybenzoate) In the same manner as shown in Examples 1 through 6 other dialkyl-4-alkenoxybenzoic acid esters of methyl deserpidate, methyl raunescate, and methyl raujernidate are prepared by reacting the latter with the appropriate acid chloride esterifying agent, including the following O-esters of methyl deserpidate, methyl raunescate and methyl ranjernidate: 2,6-dimethyl-4-propenoxybenzoate, 2,6-dimethyl-4-(B-butenoxy)-benzoate, 2,6-dimethyl-4-(flisobutenoxy)-benzoate, 2,6-diethyl-4-(5-secondary-butenoxy)-benzoate, 2,6-dibutyl-4-allyloxybenzoate, 3,5-dimethyl-4-allyloxybenzoate, 3,5-dirnethyl-4-(a-butenoxy)- benzoate, 3,5-diethyl-4-allyloxybenzoate, 3,5-dimethyl-4- (e-butenoxy) benzoate, 3,5-diethyl-4-allyloxybenzoate, 3,5-dihexyl-4-('y-butenoxy)-benzoate, 3,5-dipropyl-4-(B- isobutenoxy)-benzoate, 2,3-dimethyl-4-a1lyloxybenzoate, 2-methyl-3-ethyl-(fi-butenoxy)-benzoate, 2,3-diisobutyl-4- (fl-isobutenoxy)-benzoate, 2-isopropyl-5-methyl-4-allyloxy-benzoate, 2,5-dipropyl-4-allyloxybenzoate, 2,5:dimethyl-4-allyloxybenzoate, 2,5-diethyl-4-aliyloxybenzoate,

6 2-methyl-5-isopropyl-4-propenoxybenzoate, and other 2,3-, 2,5-, 2,6-, and 3,5-dia1kyl-4-alkenoxybenzoates. 'By substituting other alkyl deserpidates, alkyl raunescates, and alkyl raujemidates, for example, ethyl, propyl, butyl, isobutyl, and hexyl deserpidates, raunescates, and raujemidates there are obtained the corresponding 0-(dialkyl-4- alkenoxybenzoates) which have like utility.

It is to be understood that the invention is not to be limited to the exact details of operation or exact com pounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

This application is a continuation-in-part of Serial Numher 650,847, filed April 5, 1957, now abandoned.

We claim:

1. Lower-alkyl reserpate O-[di-(lower-alkyl)-4-(loweralkenoxy) -benzoate].

2. Methyl reserpate O-Edi-(lower-alkyl)-4-(lower-al kenoxy) -benzoate] 3. Methyl reserpate 0-[2,3-di-(lower-alkyl)-4-(loweralkenoxy) 'benzoate] 4. Methyl reserpate O-[2,5-di-(lower-alkyl)-4-(loweralkenoxy) -b enzoate] 5. Methyl reserpate O-[2,6-di-(lower-a1kyl)-4-(lowerreserpate O-(2,6-dimethyl-4-allyloxyben- References Cited in the file of this patent UNITED STATES PATENTS 2,789,112 Taylor Apr. 16, 1957 2,883,386 Szmuszkovicz Apr. 21, 1959 FOREIGN PATENTS 744,290 Great Britain Feb. 1, 1956 OTHER REFERENCES Hosansky et al.: Iour. Pharm. Assoc., vol. 44, No. 10, pp. 639-644 1955)., 

1. LOWER-ALKYL RESERPATE O-(DI-(LOWER-ALKYL)-4-(LOWERALKENOXY)-BENZOATE). 